Antiphospholipid Antibody Carriers Research Articles

Altered CD226/TIGIT expressions were associated with NK phenotypes in primary antiphospholipid syndrome and affected by IL-4/JAK pathway.

Natural killer (NK) cells were reported to be involved in the pathogenesis of primary antiphospholipid syndrome (pAPS). Immunosuppressive receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and activating receptor cluster of differentiation 226 (CD226) are specifically expressed on NK cells with competitive functions. This study aims to investigate the expression diversities of CD226/TIGIT on NK subsets and their associations with NK subsets activation phenotypes and potential clinical significance, furthermore, to explore potential cause for CD226/TIGIT expression diversities in pAPS. We comparatively assessed the changes of CD56brightNK, CD56dimNK, and NK-like cells in 70 pAPS patients compared with control groups, including systemic lupus erythematosus, asymptomatic antiphospholipid antibodies carriers (asymp-aPLs carriers), and healthy controls and their expression diversities of CD226/TIGIT by flow cytometry. CD25, CD69, CD107α expression, and interferon gamma (IFN-γ) secretion levels of NK subsets were detected to determine the potential association of CD226/TIGIT expression with NK subsets phenotypes. CD226/TIGIT expression levels were compared among different subgroups divided by aPLs status. Moreover, in vitro cultures were conducted to explore the potential mechanisms of CD226/TIGIT expression imbalance. CD56brightNK and CD3+CD56+NK-like cells were significantly increased while CD56dimNK cells were obviously decreased in pAPS, and CD56brightNK and NK-like cells exhibited significantly higher CD226 but lower TIGIT expressions. CD226+CD56brightNK and TIGIT-CD56brightNK cells show higher CD69 expression and IFN-γ secretion capacity, and CD226+NK-like and TIGIT-NK-like cells showed higher expressions of CD25 and CD69 but lower apoptosis rate than CD226- and TIGIT+CD56brightNK/NK-like cells, respectively. The imbalanced CD226/TIGIT expressions were most significant in aPLs triple-positive group. Imbalanced expressions of CD226/TIGIT on CD56brightNK and NK-like cells were aggravated after interleukin-4 (IL-4) stimulation and recovered after tofacitinib blocking. Our data revealed significant imbalanced CD226/TIGIT expressions on NK subsets in pAPS, which closely associated with NK subsets phenotypes and more complicated autoantibody status. CD226/TIGIT imbalanced may be affected by IL-4/Janus Kinase (JAK) pathway activation.

Antiphospholipid antibody carriers and patients with quiescent antiphospholipid syndrome show persistent subclinical complement activation.

Complement activation has been advocated as one mechanism by which aPLs can induce thrombosis. In patients with catastrophic APS or re-thrombosis, enhanced complement activation has been shown, even in the quiescent phase of the disease. We aimed to assess complement activation and to investigate its association with clinical variables in aPL-positive patients with a favourable disease course. Subjects with at least two consecutive positive aPL results obtained ≥12 weeks apart were enrolled. They were subjects without a history of thrombosis or pregnancy morbidity (aPL carriers), patients with pregnancy morbidity alone, i.e. obstetric APS patients (OAPS patients), and/or patients with arterial, venous, or small-vessel thrombotic APS (TAPS patients); for enrolment, all patients were required to have been free of symptoms for ≥2 years. Patients affected with systemic autoimmune diseases were excluded. Healthy age- and sex-matched subjects were included as controls. Plasma C5a and C5b-9 levels were assessed by commercially available ELISA assays. The non-parametric Mann-Whitney test and Spearman's correlation were applied. Thirty-seven OAPS patients, 38 TAPS patients, 42 aPL carriers and 30 healthy subjects were enrolled. The median C5a and C5b-9 levels were significantly higher in quiescent aPL-positive patients (OAPS, TAPS, aPL carriers) compared with controls: C5a ng/ml 10.61 [interquartile range (IQR) 6.87-15.46] vs 4.06 (2.66-7.35), P < 0.001; C5b-9 ng/ml 283.95 (175.8-439.40) vs 165.90 (124.23-236.8), P < 0.001. Similar C5a and C5b-9 levels were observed in OAPS and TAPS patients and aPL carriers. A positive correlation between the median C5b-9 levels and the number of aPL-positive tests was found (P = 0.002). The persistence of aPL antibodies is associated with a persistent subclinical activation of the complement cascade.

Close link between antiphosphatidylserine/prothrombin antibodies, lupus anticoagulant, and activated protein C resistance in tetra antiphospholipid antibody–positive subjects

BackgroundMost of the carriers/patients triple-positive for antiphospholipid antibodies (lupus anticoagulant [LAC], immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin, and anti–β2-glycoprotein I antibodies) are tetra-positive, being positive for antiphosphatidylserine/prothrombin (aPS/PT) antibodies. The relationship between aPS/PT titer, LAC potency, and resistance to activated protein C (aPC-R) has not been investigated. ObjectivesThe aim of this study was to clarify the mutual interdependence of these parameters in tetra-positive subjects. MethodsTwenty-three carriers and 30 patients with antiphospholipid syndrome, none of whom were being treated with anticoagulants, and 30 age- and sex-matched controls were studied. Detection of aPS/PT, LAC, and aPC-R in each individual was performed with established methods in our laboratory. Carriers and patients were positive for IgG or IgM aPS/PT or for both isotypes without significant difference. Since both IgG and IgM aPS/PT have anticoagulant activity, we used the sum of their titers (total aPS/PT) for the correlation studies. ResultsTotal aPS/PT in all individuals studied exceeded that in controls. There was no difference in total aPS/PT titers (P = .72), LAC potency (P = .56), and aPC-R (P = .82) between antiphospholipid antibody–carriers and patients with antiphospholipid syndrome. There was a significant correlation between total aPS/PT and LAC potency (r = 0.78; P < .0001) and between total aPS/PT titers and aPC-R (r = 0.80; P < .0001). LAC potency also was correlated significantly with aPC-R (r = 0.72; P < .0001). ConclusionThis study shows that there is interdependence between aPS/PT, LAC potency, and aPC-R.

Adjusted global antiphospholipid syndrome score (aGAPSS) is useful to predict relapses in patients with retinal vein occlusion

BackgroundA significant proportion of patients with retinal vein occlusion (RVO) are antiphospholipid antibodies (aPL) carriers. Relapsing disease occurs in nearly 10 % of cases and the role of aPL has not been established. The adjusted global antiphospholipid syndrome score (aGAPSS) was developed to assess the risk of clinical events in aPL carriers and its role in the management of RVO patients is unknown. ObjectiveTo analyze the values of aGAPSS in a large cohort of patients with RVO and population-based controls, and to assess its usefulness to predict RVO relapses. MethodsCase-control study of RVO patients and population-based controls of similar age and sex. We have assessed and compared the aPL profile and the aGAPSS score in patients with and without relapsing disease and controls. ResultsFour-hundred and seventy-two RVO patients and 346 controls were included. Fifty-seven RVO patients had antiphospholipid syndrome (RVO-APS). Of them, 75.4 % had a high-risk profile compared to 3 % in controls (p = 0.0001). The median aGAPSS values were 8 [7–13], 3 [1–4], and 3 [0–4], in RVO-APS, RVO no-APS, and controls. Nineteen patients had had a recurrence of RVO before inclusion and 8 during the follow-up. APS was more prevalent in relapsing patients. In the adjusted multivariable regression model, the best predictor for RVO recurrence during the follow-up was an aGAPSS score ≥6 (OR 5.5, CI95% 1.3–23.7; p = 0.023). ConclusionsIn patients with RVO, once the control of vascular risk factors has been optimized, the aGAPSS might help to identify those at risk of relapsing disease.

Cognitive Impairment in Anti-Phospholipid Syndrome and Anti-Phospholipid Antibody Carriers.

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.

Does Adjusted Global Antiphospholipid Syndrome Score (aGAPSS) Predict the Obstetric Outcome in Antiphospholipid Antibody Carriers? A Single-Center Study

The adjusted Global Antiphospholipid Syndrome (APS) Score (aGAPSS) is a tool proposed to quantify the risk for antiphospholipid antibody (aPL)-related clinical manifestations. However, aGAPSS has been validated mainly for thrombotic events and studies on APS-related obstetric manifestations are scarce. Furthermore, the majority of them included patients with positive aPL and different autoimmune diseases. Here, we assess the utility of aGAPSS to predict the response to treatment in aPL carriers without other autoimmune disorders. One-hundred and thirty-seven women with aPL ever pregnant were included. Sixty-five meet the APS classification criteria, 61 had APS-related obstetric manifestations, and 11 were asymptomatic carriers. The patients’ aGAPSS risk was grouped as low (< 6, N = 73), medium (6–11, N = 40), and high risk (≥ 12, N = 24). Since vascular risk factors included in the aGAPSS were infrequent in this population (< 10%), the aGAPSS score was mainly determined by the aPL profile. Overall, the live birth rate was 75%, and 37.2% of the patients had at least one adverse pregnancy outcome (APO). When considering patients according to the aGAPSS (high, medium, and low risk), no significant differences were found for pregnancy loss (29.2%, 25%, and 21.9%) or APO (33.3%, 47.5%, and 32.9%). In the present study, including aPL carriers without other autoimmune diseases, aGAPSS is not a valuable tool to identify patients at risk for obstetric complications despite treatment. In these patients with gestational desire, in addition to the aPL profile, other pregnancy-specific factors, such as age or previous obstetric history, should be considered.

Risk Factors for the Development of the Disease in Antiphospholipid Antibodies Carriers: A Long-term Follow-up Study

The natural history of antiphospholipid antibodies (aPL) carriers is not well-established. The objectives of the present study were (a) to study the probability of developing clinical criteria of antiphospholipid syndrome (APS), (b) to identify potential risk factors for developing thrombosis and/or obstetric complications, (c) to study the association between the antibody profile and development of APS, and (d) to determine the efficacy of primary prophylaxis. We retrospectively analyzed 138 subjects with positive aPL who did not fulfill clinical criteria for APS. The mean follow-up time was 138 ± 63.0 months. Thirteen patients (9.4%) developed thrombosis after an average period of 73.0 ± 48.0 months. Independent risk factors for thrombosis were smoking, hypertension, thrombocytopenia, and triple aPL positivity. Low-dose acetyl salicylic acid did not prevent thrombotic events. A total of 28 obstetric complications were detected in 92 pregnancies. During the follow-up, only two women developed obstetric APS. Prophylactic treatment in pregnant women was associated with a better outcome in the prevention of early abortions. The thrombosis rate in patients with positive aPL who do not meet diagnostic criteria for APS is 0.82/100 patients-year. Smoking, hypertension, thrombocytopenia, and the aPL profile are independent risk factors for the development of thrombosis in aPL carriers. Although the incidence of obstetric complications in this population is high (31.6%), only a few of them meet APS criteria. In these women, prophylactic treatment might be effective in preventing early abortions.

Thrombotic Risk Factors, Antithrombotic Therapy, and Outcomes of Asymptomatic Carriers of Antiphospholipid Antibodies and Patients with Antiphospholipid Syndrome

Background: There is marked heterogeneity in the clinical presentation of patients with antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) and a variable thrombotic risk. Putative thrombotic risk factors include male gender, high titer aPL serology with IgG isotype, triple positivity and concomitant autoimmune disease. However, the evidence is conflicting for some, and the patient heterogeneity makes risk stratification challenging. Thus, long-term antithrombotic management decisions remain primarily driven by clinical judgment. Decisions such as discontinuation of therapy, use of direct oral anticoagulants (DOAC), and the role of hydroxychloroquine (HCQ) and immunosuppressive therapy remain areas of ongoing research.Objectives: To outline clinical risk factors of thrombotic events in antiphospholipid patients and describe outcomes of different antithrombotic strategies in this heterogeneous cohort.Methods: We retrospectively identified all adult patients followed at Weill Cornell Hematology with aPL or APS. Patients were included if they met laboratory criteria for APS. Data on patient demographics, concomitant thrombophilia, autoimmune disease, and family history of thrombosis, aPL isotype and titer, thrombotic events prior to and during follow-up, and antithrombotic therapies were collected. Time to event analysis was used to identify clinical risk factors for thrombosis. The time varying effects of antithrombotic therapies were also evaluated.Results: A total of 122 patients were identified with a median age of 43 (range 19-86 yrs.). Ninety-three (76%) were female and 29 (24%) were male. Eighty-four patients (69%) were diagnosed with APS prior to their initial visit and the remaining 38 (31%) were aPL positive. Of the 84 APS patients, 63 (74%) had a history of a single thrombotic event and 22 (20%) had recurring events. Those were venous thromboembolic events (VTE) in 45 patients (53%), Arterial (AT) in 19 (22%), pregnancy morbidity (PM) in 12 (14%), and combinations of VTE, AT, and PM in the remaining 9 patients (11%). Of the 38 aPL positive carriers, 25 (66%) were asymptomatic, tested mainly for prolonged aPTT (68%), and 13 (44%) had non-criteria events that prompted testing. Autoimmune disease was present in 37 (30%), of which 16 (43%) were SLE. Hereditary thrombophilia was identified in 7 (6%) and a family history of thrombosis, aPL positivity, or APS was noted in 15 (12%).During a median follow-up duration of 47 months, 19 patients had an event (16%). A significantly higher rate of thrombosis was observed in patients with autoimmune disease (HR 4.64, p<0.01), and in Blacks vs. Whites (HR 8.37 p<0.01). Triple positivity, found in 45 patients (37%), was not associated with an increased thrombotic risk. The risk of thrombosis was significantly lowest among patients on therapeutic dose anticoagulant therapy (ac) with low-molecular weight heparin (LMWH) or vitamin K antagonist (VKA) (Figure 1). In comparison, patients on antiplatelet therapy (apt) alone had 5.4 times the risk (HR 5.432, p=0.01). DOACs were used in 9 (10%) of the APS patients, with a median follow-up of 19 months (2-37) and a single event occurring in a young male without the aforementioned risk factors. Thirteen patients (11%) were on HCQ, 8 (7%) with autoimmune disease and 5 (4%) without, for a median duration of 20 months, with a single event occurring in a patient on HCQ alone.Conclusions: In this study, concomitant autoimmune disease and Black race were risk factors for thrombotic events in antiphospholipid patients. Anticoagulation with LMWH or VKA remains the most effective therapy. Deciding on who can safely discontinue anticoagulation and who may benefit from additional antithrombotic and immunosuppressive therapies remains a matter of clinical judgment until multicenter, prospective studies are carried out. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers’ pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Identifying additional risk factors for arterial and venous thrombosis among pediatric antiphospholipid antibodies carriers.

Antiphospholipid antibodies (aPL) have been extensively reported in children, but investigations into thrombotic risks associated with aPL positivity in pediatric patients is scarce. Positive aPL are not uncommon in pediatric connective tissue diseases (CTD), but identification and management of these patients is challenging due to lack of validated criteria and a paucity of data. In this study, we identify potential additional risk factors for thrombosis in a unique cohort of pediatric aPL positive carriers. Retrospective chart review was performed on 491 pediatric patients with CTD seen in our institution from 2001 to 2019. Patients without persistently moderate to high titer aPL at least 12 weeks apart were excluded. Univariate analysis was performed to evaluate correlation between different risk factors and thrombotic events. Seventy-one aPL positive children with underlying CTD are included in this cohort. The majority (87%) are female and of Hispanic ethnicity (56%). Mean age of the cohort at the diagnosis of connective tissue disease is 12.7 (SD 2.6) years, and mean age of first positive aPL is 13.3 (SD 2.5) years. Average length of follow-up is 4.3 (SD 2.5) years. Four (5.6%) patients experienced arterial thrombosis, and 11 (15.5%) had venous thrombosis. Fifty-seven (80.3%) patients did not have any thromboembolic events. Among traditional risk factors and signs of endothelial injury, only Raynaud's phenomena demonstrated significant association with arterial thrombosis (OR = 8.4, 95%CI 1.13-111, P = 0.039), and hypertension or anti-hypertensive use demonstrated significant association with venous thrombosis (OR = 8.387, 95%CI 1.2 - 94, P = 0.02). Data from our cohort suggest that Raynaud's phenomenon is a potential predictor of arterial thrombosis while the presence of hypertension or anti-hypertensive medication use is a potential predictor of venous thrombosis in aPL positive pediatric carriers. Further studies investigating pediatric aPL profiles and risk factors for development of thrombosis are needed to help guide clinicians in caring for these challenging patients.

The impact of various entities of antiphospholipid antibodies positivity on adverse pregnancy outcome. An epidemiological perspective

The aim of the study was to evaluate the rate of obstetric complications and the burden of obstetric outcomes in antiphospholipid syndrome (APS), non-criteria APS and asymptomatic antiphospholipid antibodies (aPL) carriers. From 2013–2018, 163 pregnant subjects with aPL antibodies and 785 controls were enrolled. Penalized logistic regression was used to compare obstetric complications.Cases included 62 complete APS (38 %), 48 non-criteria APS (29.4 %) and 53 (32.5 %) asymptomatic aPL-carriers. Connective tissue diseases (CTDs) were diagnosed in 31.3 % of cases. The rate of high-risk aPL profile was higher (p < .01) in APS (67.7 %) compared to non-criteria (14.6 %) and aPL-carriers (9.4 %). Double/triple positivity was 33.9 % (p < .05 compared to non-criteria and aPL-carriers) in APS, 10.4 % in non-criteria and 9.4 % in aPL-carriers. The rate of adverse pregnancy outcomes were 5.6 % in controls, 41.9 % (adj.OR = 6.95 %CI = 2.7−13.5) in APS, 25 % (adj.OR = 4.4,95 %CI = 2−9.4) in non-criteria and 28.3 % (OR = 4.95 %CI = 1.8−8.8) in aPL-carriers. CTDs were independently associated with an increased risk of adverse obstetric outcomes (OR = 2.8,95 %CI = 1.36–5.89). The attributable fraction (AF) of adverse obstetric events was higher among low-risk antibodies compared to high-risk (AF = 0.27,95 %CI = 0.22−0.31 vs AF = 0.16,95 %CI = 0.16−0.2,p < .01) and among single positivity compared to double/triple positivity (AF = 0.32,95 %CI = 0.26−0.37 vs AF = 0.11,95 %CI = 0.09−0.13,p < .01) suggesting that low-risk subjects are responsible for a high burden of obstetric complications.

Risk Assessment and Antithrombotic Strategies in Antiphospholipid Antibody Carriers.

Antiphospholipid antibodies (aPL) are a cluster of autoantibodies directed against plasma proteins with affinity for membrane phospholipids. The most frequently tested aPL are lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), and anti-β2-glycoprotein I antibodies (anti-β2GPI). aPL play a key pathogenic role in the development of the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by recurrent thrombotic and/or pregnancy complications in patients with persistent aPL. However, aPL positivity is occasionally documented in patients with no previous history of thrombotic or pregnancy morbidity. LA activity, multiple aPL positivity, high-titer aPL, and a concomitant systemic autoimmune disease are recognized risk factors for future thrombotic events in asymptomatic carriers. Moreover, an accelerated atherosclerosis with increased cardiovascular (CV) risk has also been associated with aPL positivity, thus exposing aPL carriers to fatal complications and chronic disability requiring cardiac rehabilitation. Overall, an accurate risk stratification is recommended for aPL-positive subjects in order to prevent both venous and arterial thrombotic complications. In this review, we provide an overview of the main antithrombotic and risk assessment strategies in aPL carriers.

Antibody profiles comprising anti phosphatidylserine/prothrombin differently affect thrombin generation and protein C resistance in antiphospholipid antibody carriers

Anti phosphatidylserine/prothrombin antibodies (aPS/PT) are currently not included in the laboratory work-up of antiphospholipid symdrome (APS). However, several studies indicate that aPS/PT confer additional risk for thromboembolic events when added to classical antiphospholipid (aPL) antibody panel. We aimed to study thrombin generation (TG), a test that describes hyper or hypo-coagulability, in a cohort of antiphospholipid antibody (aPL) carriers with or without aPS/PT. As oral anticoagulants interfere with TG, we performed the study in carriers of aPL antibodies not on oral anticoagulants treatment.TG in tissue factor-triggered platelet-poor plasma and its inhibition by thrombomodulin was measured with a calibrated automated thrombogram method. Data are expressed as minutes (Interquartile Range).Of 55 aPL carriers, 37 were positive and 18 were negative for aPS/PT. Lag Time 5.4 min (4.1; 7.3) vs 3.4 min (3.0;4.5) is significant longer (p < 0.0001) and time to peak 9.6 min (8.1;11) vs 7.7 min (6.8;8.8) is significantly delayed (p = 0.0011) in aPS/PT positive as compared to aPS/PT negative carriers. Endogenous Thrombin Potential (ETP), peak thrombin formation and the velocity index are lower in aPS/PT positive carriers but did not reach statistical significance. Inhibition of ETP by thrombomodulin was significantly lower (protein C resistance) in aPS/PT positive vs aPS/PT negative group (22.8%±11.5 vs 34.9%±20.4, p = 0.01).In conclusion, aPS/PT positive carriers show an anticoagulant effect in TG while they exert a procoagulant effect in response to thrombomodulin-activated protein C.

Cardiovascular disease and antiphospholipid syndrome: how to predict and how to treat?

Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by a hypercoagulable state secondary to the presence of antiphospholipid antibodies and associated with vascular thromboses and / or pregnancy complications. Although venous thrombosis represents approximately 60% of thrombotic manifestations, also cardiovascular events can occur in patients with APS, including coronary and / or noncoronary complications. Moreover, several studies consistently showed a more significant atherosclerosis in patients with APS than controls. Thus, a stratification of thrombotic and cardiovascular risk according to clinical and immunologic features is mandatory in order to prevent APS-related vascular events. The most appropriate antithrombotic treatment of patients with arterial APS still represents an open issue, mainly in primary prevention settings. After a thrombotic event, in the absence of an adequate antithrombotic treatment, a 50% recurrence rate is reported in APS patients over a 5-year follow-up. Vitamin K antagonists still remain the mainstay treatment to prevent a recurrent event in patients with APS. The use of non–vitamin K oral anticoagulants in those with APS is still controversial, and identification of patients who could benefit from this therapy is still an open issue. Low-dose aspirin should be considered in arterial APS in addition to vitamin K antagonists in a high-risk subset, or alone for primary prophylaxis in high-risk antiphospholipid antibodies carriers. Furthermore, statins and immunomodulation therapies have an emerging role in the treatment of APS. Overall, ad hoc designed high-quality studies are needed to definitely determine optimal therapeutic strategies for arterial APS.

IgG phosphatidylserine/prothrombin antibodies as a risk factor of thrombosis in antiphospholipid antibody carriers

The clinical significance of IgG/IgM antiphosphatidylserine/prothrombin (aPS/PT) antibodies was prospectively evaluated in a cohort of 191 antiphospholipid antibody (aPL) carriers using commercial ELISA assays. IgG aPS/PT antibodies were detected in 40 (20.9%) and IgM aPS/PT in 102 (53.4%) of the carriers. Both IgG and IgM aPS/PT antibodies were significantly associated with triple aPL positivity (Lupus anticoagulants [LAC] plus anti-β2Glycoprotein I plus anticardiolipin antibodies) (p = 0.0000 for both). There was a significant prevalence of IgM aPS/PT in the individuals with isolated LAC positivity (p = 0.005). Fourteen of the aPL carriers (7.3%) developed a first thrombotic event. There was a significant prevalence of IgG aPS/PT antibodies but not of IgM aPS/PT in the thrombotic patients (p = 0.015). The cumulative incidence rate of thrombotic events was significantly higher in the IgG aPS/PT positive (p = 0.035) but not in the IgM aPS/PT positive carriers. Logistic regression analysis assessing the independent effect of IgG /IgM aPS/PT antibodies, triple aPL positivity, genetic/acquired thrombosis risk factors and autoimmune disorders on thrombosis development uncovered a significant association only for the risk factors (Odds Ratio = OR: 12.451, 95% Confidence Interval = CI: 2.519–61.537, p = 0.002) and for triple aPL positivity (OR: 4.725, 95% CI: 1.135–19.674, p = 0.033). Logistic regression evaluating the independent effect of IgG and IgM aPS/PT on thrombosis development uncovered a significant association only for the former (OR: 3.962, 95% CI: 1.174–13.37, p = 0.026). The risk score for thrombosis in aPL carriers could be more effective if IgG aPS/PT antibodies are added to triple aPL positivity and thrombosis risk factors.

Potential therapeutics for antiphospholipid antibody associated thrombocytopenia: A systematic review and meta-analysis

Objectives: Thrombocytopenia is frequently observed in antiphospholipid antibody (aPL) carriers. Due to the paradoxical risks of thrombosis and hemorrhage, the management of aPL-associated thrombocytopenia (APAT) is often deductive. We aimed to investigate the efficacy and safety of therapeutic approaches for APAT through a systematic review.Methods: Four therapeutic approaches for APAT, including antiplatelet agents, glucocorticoids, splenectomy and thrombopoietin receptor agonists, were selected. Clinical trials evaluating therapeutic outcomes including the remission, complications, mortality and relapse, were searched in MEDLINE, EMBASE and CENTRAL from the inception dates to 28 November 2016. A meta-analysis was performed to calculate risk ratios (RRs) and 95% confidence intervals (CIs) using random-effects models.Results: Out of 1407 papers, eight controlled clinical trials were included. In patients with APAT, the remission rates were higher in patients on glucocorticoids (RR 8.33 [95% CI 3.07–22.6]) or splenectomy (RR 8.37 [95% CI 1.61–43.7]) than in patients without those treatments. There was no significant association between glucocorticoids and thrombosis (RR 1.57 [95% CI, 0.17–14.9]) or between splenectomy and hemorrhage (RR 0.17 [95% CI 0.02–1.28]). The extracted data of mortality and relapse rate were not available for synthesis.Conclusion: Glucocorticoids or splenectomy seemed suitable therapeutic approaches for APAT.

Elevated plasma level of soluble triggering receptor expressed on myeloid cells-1 is associated with inflammation activity and is a potential biomarker of thrombosis in primary antiphospholipid syndrome

BackgroundSoluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an innate-immune receptor found in blood. Its presence reflects innate immune cell activation. We sought to investigate plasma sTREM-1 levels in patients with primary antiphospholipid syndrome (PAPS).MethodsA cross-sectional, case-control design was used. Plasma sTREM-1 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in consecutive patients diagnosed with PAPS or asymptomatic antiphospholipid antibody (APLA) carriers and controls.ResultsThe study cohort included 33 patients with PAPS, 10 asymptomatic APLA carriers, and 73 controls. Mean plasma sTREM-1 levels were significantly higher in patients with PAPS (299.2 ± 146.7 pg/ml) and thrombotic PAPS-ever (current and past thrombotic event) (327.2 ± 151.3 pg/ml) compared with controls (230.2 ± 85.5 pg/ml; p = 0.006 and p = 0.003, respectively), patients with thrombotic PAPS compared with patients with past obstetric APS (195.12 ± 58.52 pg/ml, p = 0.01) and APLA carriers (215.8 ± 51.6 pg/ml, p = 0.02), patients with current thrombotic PAPS (429.5 ± 227.5 pg/ml) compared with patients with past thrombotic PAPS (289.5 ± 94.65 pg/ml, p = 0.01), and patients with PAPS who had ever had a stroke or venous thromboembolic event compared with patients who had not (p = 0.007 and p = 0.02, respectively). On receiver operator characteristic curve analysis, plasma sTREM-1 levels differentiated patients with current thrombotic PAPS from asymptomatic APLA carriers and controls, with an area under the curve of 0.7292 (p = 0.0014) and 0.88 (p < 0.0001), respectively. Multivariate regression analysis to identify sTREM-1 predictors (thrombotic PAPS-ever, age, and sex) yielded an independent association of sTREM-1 levels with thrombotic PAPS (p < 0.0001).ConclusionsPlasma sTREM-1 levels are significantly elevated in patients with thrombotic PAPS. Levels of sTREM-1 might serve as a biomarker for thrombosis in patients with PAPS.

Prevalence and Significance of Non-conventional Antiphospholipid Antibodies in Patients With Clinical APS Criteria.

Background: The biological diagnostics of antiphospholipid syndrome (APS) takes into account the persistent positivity for anticardiolipin and/or anti-β2GP1 antibodies and/or presence of lupus anticoagulant (LA). However, some non-conventional antiphospholipid antibodies have emerged that could help in the diagnosis of APS.Objectives: To study the potential usefulness of non-conventional antiphospholipid antibodies in clinical practice.Methods: Eighty-seven patients, aged from 15 to 92 years were included and classified in following groups: 41 patients positive for the conventional antibodies with clinical criterion of APS (31 with primary APS and 10 secondary), 17 seronegative APS (SNAPS) patients (i.e., persistent negativity for the conventional antibodies with a strong clinical suspicion of APS), 11 asymptomatic antiphospholipid antibodies carriers (i.e., persistent positivity for the conventional antibodies without clinical evidence of APS), and 18 patients presenting with a first thrombotic or obstetrical event. IgG and IgM were detected to the following antigens: phosphatidylserine/prothrombin (PS/PT) by ELISA, and phosphatidic acid, phosphatidyl-ethanolamine, phosphatidyl-glycerol, phosphatidyl-inositol, phosphatidylserine, annexin V, prothrombin by immunodot. Anti-β2GP1 IgA, and anti-β2GP1 domain 1 IgG were detected by chemiluminescence.Results: Positivity for the non-conventional antibodies was correlated with APS severity; patients with catastrophic APS (CAPS) being positive for 10.7 (Median, Range: 5–14) non-conventional antibodies. 9/17 seronegative patients were positive for at least one of non-conventional antibodies. A study of non-supervised hierarchical clustering of all markers revealed that anti-PS/PT antibodies showed high correlation with the presence of LA. All patients with APS triple positivity (highest risk profile) exhibited also persistent positivity for anti-PS/PT antibodies.Conclusions: Our data obtained from a prospective cohort constituted mainly by patients with primary APS, suggest that non-conventional APS antibodies may be useful for patients classified as SNAPS. They demonstrate the potential value of aPS/PT antibodies as a strong marker of APS. We propose that anti-PS/PT antibodies could be a surrogate APS biological marker of LA to classify in high-risk profile patients treated by direct oral anticoagulants (DOACs), in whom LA detection cannot be achieved.

Clinical value of anti-domain I-β2Glycoprotein 1 antibodies in antiphospholipid antibody carriers. A single centre, prospective observational follow-up study

BackgroundThere seems to be a clear correlation between antibodies against domain I (anti-DI) of β2Glycoprotein I and severe clinical profiles in antiphospholipid syndrome (APS) patients. We investigated the clinical significance of anti-DI antibodies in a cohort of aPL carriers. MethodsOne hundred and five carriers persistently positive for IgG anti-β2Glycoprotein 1 antibodies (a-β2GPI) and/or IgG anticardiolipin (aCL) and/or lupus anticoagulants (LAC) were tested for the presence of anti-DI antibodies using the QUANTA Flash® Beta2GPI-Domain I chemiluminescence immunoassay. ResultsAnti-DI antibodies were detected in 44 aPL carriers (41.9%) and they were significantly associated to triple aPL positivity (LAC plus IgG a-β2GPI plus IgG aCL antibodies). Isolated LAC and a-β2GPI antibodies were significantly associated to anti-DI negative aPL carriers. During a 82.2 month mean follow-up, ten aPL carriers (9.5%) developed a first thrombotic event so becoming APS patients. Anti-DI antibodies, triple aPL positivity, thromboembolic risk factors and autoimmune disorders significantly prevailed in carriers becoming APS. Logistic regression analysis showed that anti-DI positivity was an independent risk factor for thrombosis. ConclusionsAnti-DI antibody positivity can be considered a new risk factor predictive of the first thrombotic event in aPL carriers, instead, negative anti-DI may be useful to identify low-risk aPL carriers.

Identifying Additional Risk Factors for Thrombosis and Pregnancy Morbidities Among Antiphospholipid Antibodies Carriers.

The evaluation of thrombotic and pregnancy risks associated with antiphospholipid antibodies (aPL)in individual patients without antiphospholipid syndrome (APS) clinical manifestation is challenging. Our aim is to identify additional risk factors or potential candidate “second hits” for APS clinical events in a large cohort of ethnically diverse aPL-positive patients. We included 219 consecutive aPL-positive patients who attended clinic at our institution. All patients had at least 1 persistent high titer (≥99 percentiles) aPL. Independent risk factors for thrombosis and pregnancy morbidities among patients with positive aPL were evaluated. When assessing risk factors associated with pregnancy morbidities, only female controls of reproductive age (age ≤45) were used. Pearson χ2 analysis and multivariable logistic regression were used to evaluate correlation between different risk factors and clinical manifestations. Of the 219 aPL-positive patients, 120 (54.8%) patients had criteria APS clinical manifestations and 99 patients did not. A total of 46.1% were Caucasian, 26.4% of African descent, 16.9% Hispanic, 1.8% Asian, and 8.7% were unspecified. Among traditional risk factors and signs of endothelial injury, only hypertension demonstrated an independent association with arterial thrombosis (odds ratio [OR] = 3.826, 95% confidence interval [CI]: 1.597-9.167, P = .0026), and lupus anticoagulant (LA) demonstrated an independent association with venous thrombosis (OR = 3.308, 95% CI: 1.544-7.085, P = .0021). None of the evaluated risk factors demonstrated a significant association with pregnancy morbidity. Hypertension is a potential predictor of arterial thrombosis and the presence of LA is a potential predictor of venous thrombosis in aPL-positive patients.